Host management of the mitochondrial genome

 描述（由申请人提供）：线粒体基因组的宿主管理线粒体的小基因组具有与其大小不成比例的影响。这不仅仅是因为它的少数基因产物在能量代谢中极其重要。线粒体基因组的明显独立性需要一个复杂的“行政”安排：细胞核创建发育计划，确保线粒体基因组对宿主需求的持续贡献。如果线粒体基因组有自由支配权，它将自私地进化，增强其复制以与邻居竞争，并放弃电子传递功能的产生，这些功能自然不会有助于该基因组的复制或传递。核“管理”在很大程度上但不完全包含这种不守规矩的行为。该建议探讨了基因组间关系的基础上知之甚少的监管相互作用。例如，我们发现线粒体DNA（mtDNA）在精子发生过程中从线粒体中消除。这种消除强制执行了母系遗传，这种遗传模式将线粒体基因组限制在一个谱系中。这种限制了自私行为的进化优势：例如，一个超级复制基因组可能在一个谱系内成功，但它不能传播到“感染”整个繁殖种群。该提案将研究这种DNA消除程序的机制，并测试使用这种DNA消除途径来控制和限制体细胞发育中的线粒体基因组。我们还将使用一系列新工具来研究生物体内不同的线粒体基因组如何竞争传输，以及细胞核如何监督这种竞争。线粒体基因组之间的专门竞争对宿主很重要。在这个过程中，在电子传输功能的基因组复制出功能较少的基因组。这种竞争提供了净化选择，消除了对宿主有害的突变。然而，在生长和发育过程中线粒体基因组之间的竞争不是基于功能。在这个阶段，自私的利益占主导地位，每个线粒体基因组都努力超越它的邻居，选择超级复制基因组。我们用两个线粒体基因组创建了“异质”系，一个具有复制优势但功能缺陷，另一个具有功能边缘但复制劣势。这两个基因组的保留取决于卵子发生中的选择强度与合子生长期间的选择。我们将研究影响这种平衡的线粒体基因组和核基因组的遗传变化。这将确定核基因，修改竞争，以监督线粒体基因组所采取的进化方向，以及它们对线粒体基因组的作用位点。这种方法将为我们提供一个分子和遗传学的立足点，控制影响代谢疾病，衰老，代谢和进化的调节中心轴的神秘过程。

 DESCRIPTION (provided by applicant): Host management of the mitochondrial genome the small genome of the mitochondria has an influence out of proportion to its size. It is not just tha its few gene products are extremely important in energy metabolism. The apparent independence of the mitochondrial genome has required a complex "administrative" arrangement: the nucleus creates developmental programs that ensure the continued contribution of the mitochondrial genome to the host's needs. If the mitochondrial genome had free reign, it would evolve selfishly, enhance its replication to out compete its neighbors, and abandon production of electron transport functions, which do not naturally contribute to the replication or transmission of this genome. Nuclear "management" largely but not completely contains such unruly behaviors. This proposal explores the poorly understood regulatory interactions underlying the intergenomic relationship. For example, we found that mitochondrial DNA (mtDNA) is eliminated from mitochondria during spermatogenesis. This elimination enforces maternal-only inheritance, an inheritance pattern that limits mitochondrial genomes to a lineage. This limitation caps the evolutionary advantages of selfish behavior: for example, a super replicating genome might succeed within a lineage but it cannot spread to "infect" the whole breeding population. This proposal will examine the mechanism of this DNA elimination program and test the use of this DNA elimination pathway to control and limit mitochondrial genomes in somatic development. We will also use a bevy of new tools to study how different mitochondrial genomes within an organism compete for transmission, and how the nucleus oversees this competition. A specialized competition among mitochondrial genomes to populate the egg is important to the host. During this process, genomes functional in electron-transport out-replicate less functional genomes. This competition provides the purifying selection that eliminates mutations detrimental to the host. However, competition among mitochondrial genomes during growth and development is not based on function. During this stage, selfish interests dominate, and each mitochondrial genome strives to out-compete its neighbor, selecting for super replicating genomes. We created "heteroplasmic" lines with two mitochondrial genomes, one with a replicative advantage but functional deficit, and one with a functional edge but a replicative disadvantage. Retention of these two genomes depends on the strength of the selection in oogenesis versus selection during zygotic growth. We will examine the genetic changes in the mitochondrial genome and in the nuclear genome that influence this balance. This will identify the nuclear genes that modify competition to oversee the evolutionary directions taken by the mitochondrial genome, and the sites of their action on the mitochondrial genome. This approach will give us a molecular and genetic foothold on the mysterious processes controlling a central axis of regulation influencing metabolic disease, aging, metabolism and evolution.